Comparing mycophenolate mofetil regimens for de novo renal transplant recipients: the fixed-dose concentration-controlled trial.
BACKGROUND
Fixed-dose mycophenolate mofetil (MMF) reduces the incidence of acute rejection after solid organ transplantation. The Fixed-Dose Concentration Controlled trial assessed the feasibility and potential benefit of therapeutic drug monitoring in patients receiving MMF after de novo renal transplant.


METHODS
Patients were randomized to a concentration-controlled (n=452; target exposure 45 mg hr/L) or a fixed-dose (n=449) MMF-containing regimen. The primary endpoint was treatment failure (a composite of biopsy-proven acute rejection [BPAR], graft loss, death, or MMF discontinuation) by 12 months posttransplantation.


RESULTS
Mycophenolic acid (MPA) exposures for both groups were similar at most time points and were below 30 mg hr/L in 37.3% of patients at day 3. There was no difference in the incidence of treatment failure (25.6% vs. 25.7%, P=0.81) or BPAR (14.9% vs. 15.5%, P>0.05) between the concentration-controlled and the fixed-dose groups, respectively. We did find a significant relationship between MPA-area under the concentration-time curve on day 3 and the incidence of BPAR in the first month (P=0.009) or in the first year posttransplantation (P=0.006). For later time points (day 10, month 1) there was no significant relationship between area under the concentration-time curve and BPAR (0.2572 and 0.5588, respectively).


CONCLUSIONS
There was no difference in the incidence of treatment failure between the concentration-controlled and the fixed-dose groups. The applied protocol of MMF dose adjustments based on target MPA exposure was not successful, partly because physicians seemed reluctant to implement substantial dose changes. Current initial MMF doses underexpose more than 35% of patients early after transplantation, increasing the risk for BPAR.
van Gelder
Teun
T
1Department of Hospital Pharmacy, Erasmus Medical Center, Rotterdam, The Netherlands. t.vangelder@erasmusmc.nl
Silva
Helio Tedesco
HT
de Fijter
Johan W
JW
Budde
Klemens
K
Kuypers
Dirk
D
Tyden
Gunnar
G
Lohmus
Aleksander
A
Sommerer
Claudia
C
Hartmann
Anders
A
Le Meur
Yann
Y
Oellerich
Michael
M
Holt
David W
DW
Tönshoff
Burkhard
B
Keown
Paul
P
Campbell
Scott
S
Mamelok
Richard D
RD
D000293:Adolescent; D000328:Adult; D001291:Attitude of Health Personnel; D004334:Drug Administration Schedule; D016903:Drug Monitoring; D004359:Drug Therapy, Combination; D005240:Feasibility Studies; D005260:Female; D006084:Graft Rejection / Q000209:etiology / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D016030:Kidney Transplantation / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D010818:Practice Patterns, Physicians'; D011446:Prospective Studies; D017211:Treatment Failure; D016896:Treatment Outcome
D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid